Essential tremor (ET) is one of the most common neurological disorders. It is characterized by an action tremor that most commonly affects arms but also other body parts, impacting the life quality of tens of millions of American people. Despite its high prevalence, the underlying neural mechanisms of ET are poorly understood, and as a result, current medications and surgical treatments are of limited effectiveness. The major obstacle to the study of ET etiology is the absence of a genetic animal ET model. The proposed study aims to elucidate the neural mechanisms underlying ET using a novel genetic mouse ET model. Synaptotagmin 2 (Syt2) has been previously characterized as the fast calcium-sensing protein that facilitates synaptic release. Homozygous Syt2 conditional knockout (cKO) mice crossed with parvalbumin (PV)-cre positive mice (referred to as Syt2-PV mice) exhibit specific action tremor behavior and are potentially a great mouse ET model. Combining mouse genetics, mouse behaviors, viral manipulation and circuit tracing techniques, the proposed study will validate Syt2-PV mice as a great ET animal model and utilize Syt2-PV mice to identify the specific brain region, cell type and projection pathway that generate ET-like behavior (aim 1). The identification of neural circuit components underlying ET will allow investigation of the synaptic mechanisms of ET (aim 2), using slice physiology, viral manipulation and optogenetics. These experiments will seek to establish a more faithful mouse ET model, reveal the neural circuit components and synaptic mechanisms underlying ET and shed lights into the therapeutic interventions of ET.